The vanilloid receptor, the receptor for capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), has long been assumed to exist. Finally, it was cloned in 1997 and called vanilloid receptor subtype 1 (hereinafter referred to as “VR-1”) by Caterina et al. (Caterina et al., Nature, 1997, 389, 816). Located on small unmyelinated nerve fibers (C-fibers) and myelinated nerve fibers (A-fibers), VR-1 is known as an ion channel which plays an important role in sensitizing pain stimuli by introducing the strong influx of cations such as calcium and sodium ions into the nerve endings upon activation in response to external or internal stimuli. External stimuli capable of activating VR-1 are reported to include heat and acids as well as vanilloid compounds (Tominaga et al., Neuron, 1998, 21, 531). As internal stimuli to VR-1, there are leukotriene metabolites such as 12-hydroperoxyeicosa tetraenoic acid (12-HPETE) (Hwang at al., PNAS, 2000, 97, 3655), and arachidonic acid derivatives such as anandamide (Premkumar et al., Nature, 2000, 408, 985).
On the basis of these physiological activities, VR-1 has attracted intensive attention as an integral controller playing a pivotal role in transferring various external injurable stimuli into nerve cells. According to a report, VR-1 knock-out mice responded like normal mice to general stimuli, but showed greatly reduced pain response to heat or thermal hyperalgesia, which reflects the importance of VR-1 against noxious stimuli (Caterina et al., Science, 2000, 288, 306).
VR-1 is concentratively expressed in primary sensory neurons (Caterina et al., Nature, 1997, 389, 816), which are responsible for controlling functions of internal organs such as the skin, the bones, the bladder, the gastrointestinal tract, the lungs, and so on. In addition, being distributed in other neurons on the central nervous system, the kidneys, the stomach, and T-cells (Nozawa et al., Neuroscience Letter, 2001, 309, 33; Yiangou et al., Lancet (North America Edition), 2001, 357, 1338; Birder et al., PNAS, 2001, 98, 13396) and throughout the entire body, VR-1 is inferred to play an important role in cell division and cellular signal control.
Indications found, thus far, to be associated with the control mechanism of the activity of VR-1 include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraines, arthralgia, neuropathy, nerve injury, diabetic neuropathy, neurological illness, neurodermatitis, strokes, bladder hypersensitivity, irritable bowel syndrome, respiratory disorders such as asthma, chronic obstructive pulmonary disease, etc., irritation to the skin, eyes, and mucous membranes, itching, fever, gastric-duodenal ulcer, inflammatory intestinal diseases, and urge incontinence (Korean Pat. Laid-Open Publication No. 10-2004-0034804), and an anti-obestic effect (Pharmacol. Rev., 1986, 38, 179).
Based on pharmaceutical mechanisms, both agonists and antagonists of VR-1 may be used for the treatment of the above-mentioned diseases. Pain alleviating effects of VR-1 agonists show the pharmaceutical mechanism based on the desensitization of capsaicin-sensitive sensory nerves. That is, VR-1 agonists cause pain and irritation of sensory nerves so as to desensitize them to other noxious stimuli. Due to the induction of pain in the early stage, VR-1 agonists are developed only as local analgesics. In contrast, acting through the mechanism of blocking sensory nerves from recognizing pain signals, VR-1 antagonists do not cause early pain or irritation, and have been studied for use in the treatment of systemic diseases.
As compounds capable of modulating VR-1 activity, agonists such as capsaicin, DA-5018, resiniferatoxin, etc. are used as pain drugs or are under clinical study (Szallasi, J. Med chem., 2004, 47, 2717), while various agonists including amine compounds such as heterocycloalkylbenzoimidazole (WO2004095549), amide (WO03068749, WO2004069792, WO2006006740, WO2006006741, WO2004108133, US20060122231, US20050288281, GB200319150, SE200301246), (thio)urea (WO03080578, WO02072536, WO03022809, WO03055484, WO03029199, WO03053945, WO2004052845, WO2004007459, WO2005014580, U.S. Pat. Nos. 6,984,647, 7,015,233, GB200110901, GB200305426, CA2417507, JP2003-055209, KR0556158), quinazoline, heteroaryl etc. (WO03062209, WO2004055003, WO2004055004, WO2004033435, WO05003084, WO2004072068, WO2004002983, WO0208221, WO05009977, WO0216317, US20040157845, US20050113576, U.S. Pat. No. 6,933,311, U.S. Pat. No. 7,053,088, US20060084640, US20060089360, US20060058308, U.S. Pat. No. 6,974,818, GB200107505, GB200326217, GB200407748) as well as capsazepine and iodoresiniferatoxin are under study.
Recently, the present inventors have reported an antagonist having a structure of benzoimidazole as disclosed in WO2006/080821A1, in which the antagonist shows a powerful antagonistic effect on a vanilloid receptor in HEK cells, and a powerful analgesic effect in a writhing test using an animal model.